BACKGROUND Treatment of HIV with some protease inhibitors has been associated with dyslipidemia, insulin resistance and fat redistribution. It has been hypothesized that some protease inhibitors may alter the differentiation of subcutaneous and visceral adipocytes in a disparate manner. The aim of this study was to investigate whether isolated human preadipocytes display regio-specific sensitivity to the effects of ritonavir and atazanavir by examining differentiation, as well as adipokine secretion, following a 10-day drug exposure. METHODS Paired subcutaneous and omental human preadipocytes (n = 8) were induced to differentiate for 6 days, before being exposed to atazanavir or ritonavir (1-10 micromol/l) for 10 days. Lipid metabolism was assessed by Oil Red O staining and glycerol 3-phosphate dehydrogenase enzyme activity, whereas leptin and adiponectin secretion were assessed by enzyme-linked immunosorbent assay. RESULTS There was no difference in differentiation between subcutaneous and omental adipocytes. Repeated exposure to ritonavir, but not to atazanavir, led to significant reductions in adipocyte differentiation. There were no differences in adiponectin secretion for any of the atazanavir treatments in both subcutaneous and omental adipocytes, whereas significant reductions were evident at 10 mumol/l for ritonavir exposed subcutaneous adipocytes. In contrast, both atazanavir and ritonavir were associated with altered leptin secretion. CONCLUSIONS Ritonavir, but not atazanavir exposure, can inhibit differentiation of subcutaneous and omental adipocytes to a similar extent. Regio-specific differences, however, were apparent for adiponectin and leptin secretion. The role of region-specific alterations in adipokine secretion and apoptosis in the pathogenesis of HIV-lipodystrophy requires further attention.